St. John’s Wort

The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. In this installment, Jun J. Mao, MD, MSCE, and Jyothirmai Gubili, MS, explore the role of St. John’s wort in treating some conditions and discuss what physicians should know if any of their patients with cancer ask about use of the botanical.

Overview

A perennial herb prevalent in Europe, West Asia, and North Africa, St. John’s wort is associated with a long medicinal history as a remedy to treat wounds, headaches, kidney problems, nerve disorders, and melancholia. The herb has been extensively studied, with its active constituents hyperforin and hypericin being the focus of most research. Data from clinical trials support its effectiveness in alleviating mild to moderate depression. A few studies also indicate its benefits in controlling vasomotor symptoms in peri- and postmenopausal women.

Marketed in supplemental form, the flowering tops of the herb are used to prepare capsules, tablets, liquid extracts, tinctures, and teas, as well as skin lotions for topical use to facilitate wound healing. Although primarily taken for depression, St. John’s wort is also used to address menopausal symptoms, attention-deficit hyperactivity disorder, and obsessive-compulsive disorder. However, its interactions with prescription medications, including certain chemotherapy agents, are the most documented in the literature.

The Science

In vitro andin vivo studies indicate that St. John’s wort has neuroprotective properties1 and the ability to relieve neuropathic pain.2 In addition, clinical studies suggest that St. John’s wort may be as effective as selective serotonin-reuptake inhibitors (SSRIs) such as fluoxetine3 and citalopram4 for the treatment of mild to moderate depression as well as being comparable to paroxetine5 against moderate to severe depression. Furthermore, it has been reported to be safe in the long term6 and to be a cost-effective alternative to generic antidepressants,7 with sustained reductions in depression following continued use in patients with acute moderate depression.8 However, data are inconsistent when all types of depression are analyzed,9,10 and a randomized trial failed to find any effect in patients with minor depression.11

St. John’s wort may also be useful for managing premenstrual syndrome12 and vasomotor symptoms in peri- and postmenopausal women.13

OF NOTE

St. John’s wort is widely popular as an antidepressant. However, physicians should be aware of the adverse effects associated with its use and, more importantly, its potential to interact with myriad prescription drugs that include chemotherapeutics and antidepressants, often resulting in their reduced efficacy.

Investigations into the mechanism of action revealed that St. John’s wort inhibits serotonin, norepinephrine, and dopamine reuptake by neurons in vitro.14,15 One of the active compounds, hyperforin was shown to activate transient receptor potential C6 channels and possibly influence monoamine uptake16 and to stimulate the development and function of oligodendrocytes.17 In another study, hypericin suppressed voltage-dependent calcium channel and mitogen-activated protein kinase activity resulting in glutamate release.18

Studies have also been conducted to determine how St. John’s wort induces or modulates different enzymes, altering the pharmacokinetics of corresponding drug substrates. Hyperforin was shown to induce CYP3A4 via activation of the pregnane X receptor19; a St. John’s wort extract modulated UDP-glucuronosyltransferase20 and P-glycoprotein (P-gp) activity via protein kinase C (PKC).21

Adverse Reactions

Photosensitivity orphotodermatitis and acute neuropathy have been reported with St. John’s wort.22

Acute transplant rejection: Two patients with prior heart transplantation experienced transplant rejection directly linked to the use of St. John’s wort.23 A subsequent report of 45 kidney or liver transplant recipients also described rejection linked to ingestion of St. John’s wort.24

Cardiovascular collapse: Hypotension without anaphylactic symptoms occurred shortly after induction of general anesthesia, which was potentially linked to long-term use of St. John’s wort.25

Mania was reported in three patients with underlying bipolar disorder, which resolved in two patients following discontinuation of St. John’s wort, whereas the third experienced persistent agitation for several months.22

Serotonin syndrome: Hypertension, diaphoresis, agitation, dizziness, and weakness with acute onset have been reported following 10 days of St. John’s wort intake.26

Erythroderma developed 4 days after initiation of St. John’s wort and resolved after 5 weeks of concomitant treatment with oral steroids.27

Sexual dysfunction: Decreased sexual libido was reported and normalized following discontinuation of St. John’s wort.28

Prolonged facial dystonia: A 58-year-old woman suffered prolonged facial dystonia following the use of bupropion along with St. John’s wort.30

Herb-Drug Interactions

St. John’s wort induces cytochrome P450 isoenzyme 3A4 and 2C9, thereby affecting the metabolism of certain medications and reducing serum concentrations and efficacy. Drugs metabolized by these enzymes include the following agents:

P-gp substrate drugs including digoxin,49 talinolol,50 and fexofenadine.51 St. John’s wort may also cause serious adverse effects in conjunction with pegylated interferon alpha.52

Uridine 5-diphospho-glucuronosyltransferase substrates: St. John’s wort was also shown to modulate uridine 5-diphospho-glucuronosyltransferase enzymes in vitro and may therefore increase the side effects of drugs such as acetaminophen.20

Summary

Due to its potential interactions with many prescription drugs and conventional anticancer treatments, St. John’s wort should not be recommended for patients who are undergoing active treatment or taking other types of prescription drugs. If patients strongly desire to take St. John’s wort, careful monitoring is needed to ensure its safe use.